Purpose: Checkpoint inhibitors demonstrate salutary anticancer effects, including long-term remissions. PD-L1 expression/amplification, high mutational burden, and mismatch repair deficiency correlate with response. We have, however, observed a subset of patients who appear to be “hyperprogressors,” with a greatly accelerated rate of tumor growth and clinical deterioration compared with pretherapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with “hyperprogression” after immunotherapy.Experimental Design: Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed (N = 155). We defined hyperprogression as time-to-treatment failure (TTF) 50% increase in tumor burden compared with preimmunotherapy imaging, and >2-fold increase in progression pace.Results: Amongst 155 patients, TTF <2 months was seen in all six individuals with MDM2/MDM4 amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3-fold compared with the 2 months before immunotherapy). In multivariate analysis, MDM2/MDM4 and EGFR alterations correlated with TTF <2 months. Two of 10 patients with EGFR alterations were also hyperprogressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase).Conclusions: Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for hyperprogression on immunotherapy. Further investigation is urgently needed. Clin Cancer Res; 23(15); 4242–50. ©2017 AACR.

Strategies for unlocking immunosuppression in the tumor microenvironment have been investigated to overcome resistance to first-generation immune checkpoint blockade with anti- programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) agents. Indoleamine 2,3-dioxygenase (IDO) 1, an enzyme catabolizing tryptophan to kynurenine, creates an immunosuppressive environment in preclinical studies. Early phase clinical trials investigating inhibition of IDO1, especially together with checkpoint blockade, provided promising results. Unfortunately, the phase 3 trial of the IDO1 inhibitor epacadostat combined with the PD-1 inhibitor pembrolizumab did not show clinical benefit when compared with pembrolizumab monotherapy in patients with advanced malignant melanoma, which dampened enthusiasm for IDO inhibitors. Even so, several molecules, such as the aryl hydrocarbon receptor and tryptophan 2,3-dioxygenase, were reported as additional potential targets for the modulation of the tryptophan pathway, which might enhance clinical effectiveness. Furthermore, the combination of IDO pathway blockade with agents inhibiting other signals, such as those generated by PIK3CA mutations that may accompany IDO1 upregulation, may be a novel way to enhance activity. Importantly, IDO1 expression level varies by tumor type and among patients with the same tumor type, suggesting that patient selection based on expression levels of IDO1 may be warranted in clinical trials.

Next-generation sequencing (NGS) can identify novel cancer targets. However, interpreting the molecular findings and accessing drugs/clinical trials is challenging. Furthermore, many tumors show resistance to monotherapies. To implement a precision strategy, we initiated a multidisciplinary (basic/translational/clinical investigators, bioinformaticians, geneticists, and physicians from multiple specialties) molecular tumor board (MTB), which included a project manager to facilitate obtaining clinical-grade biomarkers (blood/tissue NGS, specific immunohistochemistry/RNA expression including for immune-biomarkers, per physician discretion) and medication-acquisition specialists/clinical trial coordinators/navigators to assist with medication access. The MTB comprehensively reviewed patient characteristics to develop N-of-One treatments implemented by the treating physician’s direction under the auspices of a master protocol. Overall, 265/429 therapy-evaluable patients (62%) were matched to ≥1 recommended drug. Eighty-six patients (20%) matched to all drugs recommended by MTB, including combinatorial approaches, while 38% received physician’s choice regimen, generally with unmatched approach/low degree of matching. Our results show that patients who receive MTB-recommended regimens (versus physician choice) have significantly longer progression-free (PFS) and overall survival (OS), and are better matched to therapy. High (≥50%) versus low (<50%) Matching Score therapy (roughly reflecting therapy matched to ≥50% versus <50% of alterations) independently correlates with longer PFS (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50–0.80;P < 0.001) and OS (HR, 0.67; 95% CI, 0.50–0.90;P = 0.007) and higher stable disease ≥6 months/partial/complete remission rate (52.1% versus 30.4%P < 0.001) (all multivariate). In conclusion, patients who receive MTB-based therapy are better matched to their genomic alterations, and the degree of matching is an independent predictor of improved oncologic outcomes including survival.

Purpose: Aberrations in genetic sequences encoding the tyrosine kinase receptor RET lead to oncogenic signaling that is targetable with anti-RET multikinase inhibitors. Understanding the comprehensive genomic landscape of RET aberrations across multiple cancers may facilitate clinical trial development targeting RET. Experimental Design: We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence of RET aberrations using Clinical Laboratory Improvement Amendments–certified targeted next-generation sequencing of 182 or 236 gene panels. Results: Among diverse cancers, RET aberrations were identified in 88 cases [1.8% (88/4, 871)], with mutations being the most common alteration [38.6% (34/88)], followed by fusions [30.7% (27/88), including a novel SQSTM1-RET] and amplifications [25% (22/88)]. Most patients had coexisting aberrations in addition to RET anomalies [81.8% (72/88)], with the most common being in TP53-associated genes [59.1% (52/88)], cell cycle–associated genes [39.8% (35/88)], the PI3K signaling pathway [30.7% (27/88)], MAPK effectors [22.7% (20/88)], or other tyrosine kinase families [21.6% (19/88)]. RET fusions were mutually exclusive with MAPK signaling pathway alterations. All 72 patients harboring coaberrations had distinct genomic portfolios, and most [98.6% (71/72)] had potentially targetable coaberrations with either an FDA-approved or an investigational agent. Two cases with lung (KIF5B-RET) and medullary thyroid carcinoma (RET M918T) that responded to a vandetanib (multikinase RET inhibitor)-containing regimen are shown. Conclusions: RET aberrations were seen in 1.8% of diverse cancers, with most cases harboring actionable, albeit distinct, coexisting alterations. The current report suggests that optimal targeting of patients with RET anomalies will require customized combination strategies. Clin Cancer Res; 23(8); 1988–97. ©2016 AACR.

Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated 54 to 70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66% (290/442) ≥1 characterized alteration(s), excluding variants of unknown significance. TP53-associated genes were most commonly altered [37.8% (167/442)], followed by genes involved in the MAPK pathway [31.2% (138/442)], PI3K signaling [18.1% (80/442)], and the cell-cycle machinery [10.4% (46/442)]. Among 290 patients harboring characterized alterations, distinct genomic profiles were observed in 87.9% (255/290) of CUP cases, with 99.7% (289/290) exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor–based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of noninvasive liquid biopsies in next-generation clinical trials. Cancer Res; 77(16); 4238–46. ©2017 AACR.